Circulating antibodies to native and denatured types I and II human and bovine collagens were assayed in patients with rheumatoid arthritis (RA), patients with other rheumatic diseases, and normal individuals. A subgroup of this population was also assayed for reactivity with typing reagents which detect determinants (MT and HLA-DR) present in human immune response gene products. The mean titers of antibodies to each collagen tested were not significantly higher in RA patients when compared with patients who had other rheumatic diseases. Although both MT3 and MT4 were significantly associated with RA, there was no significant association between the anticollagen antibodies and any MT type or HLA-DR4. These studies raise a question concerning the role of collagen antibodies in the pathogenesis of RA and suggest that genes distinct from those coding for HLA-DR may play a role in the expression of the disease.